1. Field of the Invention
This invention relates to chemotherapy and radiation therapy for treatment of cancers. More particularly, it relates to use of camptothecin derivatives as chemotherapeutic agents, together with radiation, for treatment of cancers.
2. Description of Related Art
The combination of chemotherapy and radiation therapy has become the treatment of choice for a number of cancers, particularly for advanced human malignancies. A number of chemotherapeutic drugs are known to be able to synergistically enhance the cytotoxicity of ionizing radiation. Widely-used chemotherapeutic agents, including 5-fluorouracil, etoposide, adriamycin, vinblastine, mitomycin C, cisplatin, bleomycin, and paclitaxel have all been shown to mediate radiosensitization effects via different mechanisms. Recently, improved clinical responses from chemoradiation have been obtained, and promising clinical protocols are being generated and tested in this exciting field of cancer treatment.
One repair mechanism of interest is DNA topoisomerase I. DNA topoisomerase I is a nuclear enzyme that is involved in catalyzing the interconversions of various topological states of DNA. The activity of DNA topoisomerase I is known to be important in many aspects of nucleic acid metabolism, such as DNA replication elongation, transcription elongation of RNA, and regulation of DNA supercoiling. Mammalian DNA topoisomerase I has been shown to be the cellular target of a number of anti-neoplastic compounds, including camptothecin and camptothecin derivatives.
20(S)-camptothecin (CPT), a plant alkaloid, was found to have anticancer activity in the late 1950's. Wall, M. et al., Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J. Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall et al., Camptothecin: Discovery to Clinic, 803 Annals of the New York Academy of Sciences 1 (1996). These documents, and all documents (articles, patents, etc.) cited to herein, are incorporated by reference into the specification as if reproduced fully below. The chemical formula of CPT was determined to be C.sub.20 H.sub.16 N.sub.2 O.sub.4.
Drug interference with the topoisomerase I-mediated breakage-rejoining of DNA strands is thought to be the common mechanism of drug action. Instead of direct inhibition of the catalytic activity of topoisomerase I, topoisomerase inhibiting drugs kill cells by converting an essential DNA topology modifying activity into a DNA breaking poison, which damages DNA through interactions with cellular processes such as replication of DNA. The presence of up-regulated, higher levels of topoisomerase I in both proliferating and quiescent tumor cells than in normal cells suggest that topoisomerase I-targeting drugs may possess a selected cytotoxic advantage against slow growing as well as rapidly proliferating tumors.
Camptothecin, whether substituted or unsubstituted, is believed to intervene in the mechanism of action of the nuclear enzyme topoisomerase I (topo I), arresting cells in the S phase. It is believed that CPT accomplishes this by stabilizing the covalently linked complexes of DNA-topo I (termed cleavable complexes), thus halting the progression of replication forks. This collision of the replication fork with the cleavable complexes is believed to trigger the apoptotic pathway. Z. Darzynkiewicz et al., The Cell Cycle Effects of Camptothecin, 803 Annals of the New York Academy of Sciences 93 (1996). DNA strand breaks are also implicated in the cytotoxic effects of CPT. F. Traganos et al., Induction of Apoptosis by Camptothecin and Topotecan, 803 Annals of the New York Academy of Sciences 101 (1996).
CPT itself is insoluble in water. However, during the sixties and seventies the sodium salt of CPT was derived from CPT through opening of the lactone ring using a mild base. Clinical trials were then conducted using this hydrosoluble, sodium salt derivative of CPT (CPT Na+), which was administered intravenously. The studies were later abandoned because of the high toxicity and low potency of CPT Na+. Gottlieb, J. A., et al., Preliminary pharmacological and clinical evaluation of camptothecin sodium salt (NSC 100880), Cancer Chemother. Rep. 54:461-470 (1979); Muggia, F. M., et al., Phase I clinical trials of weekly and daily treatment with camptothecin (NSC100880): Correlation with clinical studies, Cancer Chemother. Rep. 56:515-521 (1972); Gottlieb, J. A. et al., Treatment of malignant melanoma with camptothecin (NSC 100880), Cancer Chemother. Rep. 56:103-105 (1972); and Moertel, C. G., et al., Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer, Cancer Chemother Rep. 56:95-101 (1972).
Despite its potential, interest in CPT as a therapeutic remained at a low ebb until the mid-1980's. By that time, drug therapies were being evaluated for treating human cancer using human cancer xenograft lines. During these evaluations, human tumors are serially heterotransplanted into immunodeficient, so-called "nude" mice, and the mice then tested for their responsiveness to a specific drug. (Giovanella, B. C., et al., Cancer 52(7): 1146 (1983)). The data obtained in these studies strongly support the validity of heterotransplanted human tumors into immunodeficient mammals, such as nude mice, as a predictive model for testing the effectiveness of anticancer agents.
Investigators began to experiment with various substituted forms of CPT. CPT and some of its substituted forms were found to be cytostatic for nontumorigenic cells and cytotoxic for tumorigenic cells; the selective toxicity of the compounds against tumorigenic cells in vitro and in vivo was an especially interesting feature of these drugs. Good activity was found when various substitutions were made to the CPT scaffold. For example, 9-Amino-20(S)-Camptothecin (9AC) and 10,11-Methylendioxy-20(S)-Camptothecin (10,11 MD) are capable of having high anticancer activity against human colon cancer xenografts. Giovanella, B. C., et al., Highly effective topoisomerase-targeted chemotherapy of human colon cancer in xenografts, Science 246:1046-1048 (1989).
Additionally, 9-nitrocamptothecin (9NC) has shown high activity against human tumor xenograft models. 9NC has a nine position hydrogen substituted with a nitro moiety. 9NC has inhibited the growth of human tumor xenografts in nude mice and has induced regression of human tumors established as xenografts in nude mice with little or no appearance of any measurable toxicity. D. Chatterjee et al., Induction of Apoptosis in Malignant and Camptothecin-resistant Human Cells, 803 Annals of the New York Academy of Sciences 143 (1996).
Other substituted CPT compounds that have shown promise include 7-ethyl-10-hydroxy CPT, and other 7, 9, 10, 11-substituted compounds.
The possibilities of combining radiation and CPT derivatives did not go unnoticed by researchers. Alexander V. Kirichenko et al., Potentiation of Murine MCa-4 Carcinoma Radioresponse by 9-Amino-20(S)-camptothecin, Cancer Research 57:1929-1933 (1997); Allan Y. Chen et al., Mammalian DNA Topoisomerase I Mediates the Enhancement of Radiation Cytotoxicity by Camptothecin Derivatives, Cancer Res. 57:1529-1536 (1997); Kenji Tamura et al., Enhancement of tumor Radio-response by Irinotecan in Human Lung Tumor Xenografts, Jpn. J. Cancer Res. 88:218-223 (1997); John P. Lamond et al., Radiation Lethality Enhancement with 9-Aminocamptothecin: Comparison to Other Topoisomerase I Inhibitors, Int. J. Radiation Oncology Biol. Phys. 36:369-376 (1996); John P. Lamond et al., The Potential of Topoisomerase I Inhibitors in the Treatment of CNS Malignancies: Report of a Synergistic Effect Between Topotecan and Radiation, Journal of Neuro-Oncology 30:1-6 (1996); and Michael R. Mattern et al., Synergistic Cell Killing by Ionizing Radiation and Topoisomerase I Inhibitor Topotecan (SK&F 104864), Cancer Research 51:5813-5816 (1991).
However, there remains a serious problem with respect to use of currently marketed CPT derivatives, such as topotecan (available as HYCAMPTIN from Smith-Kline Beecham) or irinotecan (available as CAMPTOSAR from Pharmacia & Upjohn), for use in chemoradiation therapies. This problem is that the currently marketed CPT derivatives are administered intravenously. Therefore, depending upon the labeled dosing schedule, it is quite possible that any given radiation regimen might call for radiation administration on a day when a patient might not be given CPT. For example, HYCAMPTIN may be administered to a patient for three days on and eleven days off, while a radiation therapy is typically may be administered for five days on, two days off. If so, then every other week the patient will not receive radiation while a CPT derivative is bioavailable in pharmacologically significant amounts.
There is therefore a need for methods whereby CPT derviatives may be administered together with radiation to overcome the problems mentioned above.